Ethynyl Derivatives

ABSTRACT

The present invention relates to ethynyl derivatives of formula I 
     
       
         
         
             
             
         
       
         
         wherein 
         Y is N or CH 
           1  is fluoro or chloro 
         R 2  is hydrogen or methyl 
         or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof. 
       
    
     It has now surprisingly been found that the compounds of general formula I are metabotropic glutamate receptor antagonists (negative allosteric modulators) for use in the treatment of anxiety and pain, depression, Fragile-X syndrom, autism spectrum disorders, Parkinson&#39;s disease, and gastroesophageal reflux disease (GERD).

This application is a continuation of International ApplicationPCT/EP2013/071500, filed Oct. 15, 2013, which claims the benefit ofpriority to European Application 12188940.6, filed Oct. 18, 2012, eachof which is incorporated herein by reference in its entirety.

The present invention relates to ethynyl derivatives of formula I

wherein

-   Y is N or CH;-   R¹ is fluoro or chloro;-   R² is hydrogen or methyl;    or to a pharmaceutically acceptable acid addition salt, to a racemic    mixture, or to its corresponding enantiomer and/or optical isomer    and/or stereoisomer thereof.

It has now surprisingly been found that the compounds of general formulaI are metabotropic glutamate receptor antagonists (NAM=negativeallosteric modulators). Compounds of formula I are distinguished byhaving valuable therapeutic properties. They can be used in thetreatment or prevention of mGluR5 receptor mediated disorders.

In the central nervous system (CNS) the transmission of stimuli takesplace by the interaction of a neurotransmitter, which is sent out by aneuron, with a neuroreceptor.

Glutamate is the major excitatory neurotransmitter in the brain andplays a unique role in a variety of central nervous system (CNS)functions. The glutamate-dependent stimulus receptors are divided intotwo main groups. The first main group, namely the ionotropic receptors,forms ligand-controlled ion channels. The metabotropic glutamatereceptors (mGluR) belong to the second main group and, furthermore,belong to the family of G-protein coupled receptors.

At present, eight different members of these mGluR are known and ofthese some even have sub-types. According to their sequence homology,signal transduction mechanisms and agonist selectivity, these eightreceptors can be sub-divided into three sub-groups:

mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to groupII and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Negative allosteric modulators of metabotropic glutamate receptors,belonging to the first group, can be used for the treatment orprevention of acute and/or chronic neurological disorders such asParkinson's disease, Fragile-X syndrome, autistic disorders, cognitivedisorders and memory deficits, as well as chronic and acute pain andgastroesophageal reflux disease (GERD).

Other treatable indications in this connection are restricted brainfunction caused by bypass operations or transplants, poor blood supplyto the brain, spinal cord injuries, head injuries, hypoxia caused bypregnancy, cardiac arrest and hypoglycaemia. Further treatableindications are ischemia, Huntington's chorea, amyotrophic lateralsclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy,idiopathic parkinsonism or parkinsonism caused by medicaments as well asconditions which lead to glutamate-deficiency functions, such as e.g.muscle spasms, convulsions, migraine, urinary incontinence, nicotineaddiction, opiate addiction, anxiety, vomiting, dyskinesia anddepressions.

Disorders mediated full or in part by mGluR5 are for example acute,traumatic and chronic degenerative processes of the nervous system, suchas Alzheimer's disease, senile dementia, Parkinson's disease,Huntington's chorea, amyotrophic lateral sclerosis and multiplesclerosis, psychiatric diseases such as schizophrenia and anxiety,depression, pain and drug dependency (Expert Opin. Ther. Patents (2002),12, (12)).

Selective mGluR5 antagonists are especially useful for the treatment ofdisorders where reduction of mGluR5 receptor activation is desired, suchas anxiety and pain, depression, Fragile-X syndrom, autism spectrumdisorders, Parkinson's disease, and gastroesophageal reflux disease(GERD).

Objects of the present invention are compounds of formula I and theirpharmaceutically acceptable salts, the above-mentioned compounds aspharmaceutically active substances and their production. Further objectsof the invention are medicaments based on a compound in accordance withthe invention and their manufacture as well as the use of the compoundsin the control or prevention of mGluR5 receptor (NAM) mediateddisorders, which are anxiety and pain, depression, Fragile-X syndrom,autism spectrum disorders, Parkinson's disease, and gastroesophagealreflux disease (GERD, and, respectively, for the production ofcorresponding medicaments.

One embodiment of the present invention are compounds of formula Iwherein Y is N.

This compound is

-   (3,3-dimethyl-morpholin-4-yl)[5-(3-chloro-phenylethynyl)-pyrimidin-2-yl]-methanone.

One further embodiment of the present invention are compounds of formulaI, wherein Y is CH.

These compounds are

-   (3,3-dimethyl-morpholin-4-yl)[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-methanone-   [5-(3-chloro-phenylethynyl)-pyridin-2-yl]-morpholin-4-yl-methanone    or-   (3,3-dimethyl-morpholin-4-yl)-[5-(3-chloro-phenylethynyl)-pyridin-2-yl]-methanone.

A particular embodiment of the invention consists of the followingcompounds:

-   (3,3-dimethyl-morpholin-4-yl)[5-(3-chloro-phenylethynyl)-pyrimidin-2-yl]-methanone.-   (3,3-dimethyl-morpholin-4-yl)[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-methanone-   [5-(3-chloro-phenylethynyl)-pyridin-2-yl]-morpholin-4-yl-methanone    or-   (3,3-dimethyl-morpholin-4-yl)[5-(3-chloro-phenylethynyl)-pyridin-2-yl]-methanone.

Compounds, which are similar to those of the present invention, havebeen generically described as positive allosteric modulators of themGluR5 receptor. Surprisingly, it has been found that highly potentmGluR5 antagonists were obtained instead of mGluR5 positive allostericmodulators, which have a completely opposite pharmacology if comparedwith positive allosteric modulators.

The main difference between positive- and negative allosteric modulatorscan be seen in FIG. 1. A mGluR5 positive allosteric modulator (PAM)leads to increased receptor activity (Ca²⁺ mobilisation) in presence ofa fixed concentration of glutamate, whereas an allosteric antagonist(negative allosteric modulator, NAM) leads to a reduction of receptoractivation. FIG. 1 shows the general behavior of a NAM and a PAM underthe same conditions. The affinity for the receptor in FIG. 1 is ca. 10⁻⁷M for the PAM and between 10^(−M and) 10⁻⁸ M for the NAM. These valuescan also be measured using a binding assay to displace a radioligand(=MPEP), see the assay description.

The indications which can be addressed by the compounds are not thesame. mGluR5-NAMs are beneficial for indications where a reduction ofexcessive receptor activity is desired, such as anxiety and pain,depression, Fragile-X syndrom, autism spectrum disorders, Parkinson'sdisease, and gastroesophageal reflux disease (GERD). mGluR5 PAMs on theother hand are useful in indications where a normalization of decreasedreceptor activity is desired, such as in psychosis, epilepsy,schizophrenia, Alzheimer's disease and associated cognitive disorders,as well as tuberous sclerosis.

This difference can be practically shown for example in an anxietyanimal model, such as in the “rat Vogel conflict drinking test”, wherethe compounds of the invention show anxiolytic activity, whereasmGluR-PAMs do not show activity in this animal model.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1: Comparison of an mGluR5 positive allosteric modulator (PAM) andan mGluR5 antagonist (negative allosteric modulator=NAM).

BIOLOGICAL ASSAYS AND DATA Intracellular Ca²⁺ Mobilization Assay

A monoclonal HEK-293 cell line stably transfected with a cDNA encodingfor the human mGlu5a receptor was generated; for the work with mGlu5Positive Allosteric Modulators (PAMs), a cell line with low receptorexpression levels and low constitutive receptor activity was selected toallow the differentiation of agonistic versus PAM activity. Cells werecultured according to standard protocols (Freshney, 2000) in Dulbecco'sModified Eagle Medium with high glucose supplemented with 1 mMglutamine, 10% (vol/vol) heat-inactivated bovine calf serum,Penicillin/Streptomycin, 50 μg/ml hygromycin and 15 μg/ml blasticidin(all cell culture reagents and antibiotics from Invitrogen, Basel,Switzerland).

About 24 hrs before an experiment, 5×10⁴ cells/well were seeded inpoly-D-lysine coated, black/clear-bottomed 96-well plates. The cellswere loaded with 2.5 μM Fluo-4AM in loading buffer (1×HBSS, 20 mM HEPES)for 1 hr at 37° C. and washed five times with loading buffer. The cellswere transferred into a Functional Drug Screening System 7000(Hamamatsu, Paris, France), and 11 half logarithmic serial dilutions oftest compound at 37° C. were added and the cells were incubated for10-30 min. with on-line recording of fluorescence. Following thispre-incubation step, the agonist L-glutamate was added to the cells at aconcentration corresponding to EC₂₀ (typically around 80 μM) withon-line recording of fluorescence; in order to account for day-to-dayvariations in the responsiveness of cells, the EC₂₀ of glutamate wasdetermined immediately ahead of each experiment by recording of a fulldose-response curve of glutamate.

Responses were measured as peak increase in fluorescence minus basal(i.e. fluorescence without addition of L-glutamate), normalized to themaximal stimulatory effect obtained with saturating concentrations ofL-glutamate. Graphs were plotted with the % maximal stimulatory usingXLfit, a curve fitting program that iteratively plots the data usingLevenburg Marquardt algorithm. The single site competition analysisequation used was y=A+((B−A)/(1+((x/C)D))), where y is the % maximalstimulatory effect, A is the minimum y, B is the maximum y, C is theEC₅₀, x is the log10 of the concentration of the competing compound andD is the slope of the curve (the Hill Coefficient). From these curvesthe EC₅₀ (concentration at which half maximal stimulation was achieved),the Hill coefficient as well as the maximal response in % of the maximalstimulatory effect obtained with saturating concentrations ofL-glutamate were calculated.

Positive signals obtained during the pre-incubation with the PAM testcompounds (i.e.

before application of an EC₂₀ concentration of L-glutamate) wereindicative of an agonistic activity, the absence of such signals weredemonstrating the lack of agonistic activities. A depression of thesignal observed after addition of the EC₂₀ concentration of L-glutamatewas indicative of an inhibitory activity of the test compound.

In the list of examples below are shown the corresponding results forcompounds which all have EC₅₀ values less or equal 100 nM.

mGlu5 PAM Efficacy Example EC₅₀ [nM] [%]

46 57

50 59

inactive

inactive

inactive

inactive

MPEP Binding Assay

For binding experiments, cDNA encoding human mGlu5a receptor wastransiently transfected into EBNA cells using a procedure described bySchlaeger and Christensen [Cytotechnology 15:1-13 (1998)]. Cell membranehomogenates were stored at −80° C. until the day of assay where uponthey were thawed and resuspended and polytronised in 15 mM Tris-HCl, 120mM NaCl, 100 mM KCl, 25 mM CaCl₂, 25 mM MgCl₂ binding buffer at pH 7.4to a final assay concentration of 20 μg protein/well.

Saturation isotherms were determined by addition of twelve [³H]MPEPconcentrations (0.04-100 nM) to these membranes (in a total volume of200 μl) for 1 h at 4° C. Competition experiments were performed with afixed concentration of [³H]MPEP (2 nM) and IC₅₀ values of test compoundsevaluated using 11 concentrations (0.3-10,000 nM). Incubations wereperformed for 1 h at 4° C.

At the end of the incubation, membranes were filtered onto unifilter(96-well white micro-plate with bonded GF/C filter preincubated 1 h in0.1% PEI in wash buffer, Packard BioScience, Meriden, Conn.) with aFiltermate 96 harvester (Packard BioScience) and washed 3 times withcold 50 mM Tris-HCl, pH 7.4 buffer. Nonspecific binding was measured inthe presence of 10 μM MPEP. The radioactivity on the filter was counted(3 min) on a Packard Top-count microplate scintillation counter withquenching correction after addition of 45 μl of microscint 40 (CanberraPackard S. A., Zürich, Switzerland) and shaking for 20 min.

Comparison of Compounds of the Invention Versus the Reference Compounds1 and 2

As can be seen in the table below, the compounds of the invention (NAM)show a clearly different profile compared to structurally similarreference compounds 1 and 2 (PAM).

EC₅₀ (nM) Ki (nM) mGlu5 PAM MPEP Activity Ex. Structure assay bindingprofile Ref. 1 Ex. 35

46 201 PAM Ref. 1 Ex. 46

50 315 PAM 1

inactive  72 NAM 2

inactive  19 NAM 3

inactive  23 NAM 4

inactive  67 NAM

The compounds of formula I can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Appropriate reaction conditions for the individual reaction steps areknown to a person skilled in the art. The reaction sequence is notlimited to the one displayed in the schemes, however, depending on thestarting materials and their respective reactivity the sequence ofreaction steps can be freely altered. Starting materials are eithercommercially available or can be prepared by methods analogous to themethods given below, by methods described in references cited in thedescription or in the examples, or by methods known in the art.

The present compounds of formula I and their pharmaceutically acceptablesalts may be prepared by methods, known in the art, for example by theprocess variants described below, which process comprises

reacting a compound of formula

with a compound of formula

to form a compound of formula I

wherein the substituents are described above.

The preparation of compounds of formula I is further described in moredetail in scheme 1 and in examples 1-4.

An ethynyl-pyridine or ethynyl-pyrimidine compound of formula I can beobtained for example by Sonogashira coupling of5-bromo-pyridine-2-carboxylic acid methyl ester or5-bromo-pyrimidine-2-carboxylic acid methyl ester 1 with anappropriately substituted arylacetylene 2 followed by saponificationwith a base such as LiOH to yield the corresponding acid 3 or bySonogashira coupling of 5-bromo-pyridine-2-carboxylic acid or5-bromo-pyrimidine-2-carboxylic acid 1 with an appropriately substitutedarylacetylene 2 to yield directly the corresponding acid 3. Reacting thecorresponding acid 3 with a corresponding morpholine derivative 4 in thepresence of a base such as Hunig's Base and a peptide coupling reagentsuch as TBTU in a solvent such as dioxane or by preparing in-situ thecorresponding acid chloride with oxalyl chloride and DMF (cat.) in asolvent such as dichloromethane followed by reaction with acorresponding morpholine derivative 4 in the presence of a base such aspyridine yield the desired ethynyl compounds of general formula I(scheme 1).

Pharmaceutically acceptable salts of compounds of formula I can bemanufactured readily according to methods known per se and taking intoconsideration the nature of the compound to be converted into a salt.Inorganic or organic acids such as, for example, hydrochloric acid,hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citricacid, formic acid, fumaric acid, maleic acid, acetic acid, succinicacid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid andthe like are suitable for the formation of pharmaceutically acceptablesalts of basic compounds of formula I. Compounds which contain thealkali metals or alkaline earth metals, for example sodium, potassium,calcium, magnesium or the like, basic amines or basic amino acids aresuitable for the formation of pharmaceutically acceptable salts ofacidic compounds.

Moreover the invention relates also medicaments containing one or morecompounds of the present invention and pharmaceutically acceptableexcipients for the treatment and prevention of mGluR5 receptor mediateddisorders, such as anxiety and pain, depression, Fragile-X syndrom,autism spectrum disorders, Parkinson's disease, and gastroesophagealreflux disease (GERD).

The invention also relates to the use of a compound in accordance withthe present invention as well as its pharmaceutically acceptable saltfor the manufacture of medicaments for the treatment and prevention ofmGluR5 receptor mediated disorders as outlined above.

The pharmacological activity of the compounds was tested using thefollowing method:

cDNA encoding rat mGlu5a receptor was transiently transfected into EBNAcells using a procedure described by E.-J. Schlaeger and K. Christensen(Cytotechnology 1998, 15, 1-13). [Ca²⁺]i measurements were performed onmGlu5a transfected EBNA cells after incubation of the cells with Fluo3-AM (obtainable by FLUKA, 0.5 μM final concentration) for 1 hour at 37°C. followed by 4 washes with assay buffer (DMEM supplemented with Hank'ssalt and 20 mM HEPES. [Ca²⁺]i measurements were done using afluorometric imaging plate reader (FLIPR, Molecular Devices Corporation,La Jolla, Calif., USA). When compounds were evaluated as antagoniststhey were tested against 10 μM glutamate as agonist.

The inhibition (antagonists) curves were fitted with a four parameterlogistic equation giving IC₅₀, and Hill coefficient using the iterativenon linear curve fitting software Origin (Microcal Software Inc.,Northampton, Mass., USA).

The Ki values of the compounds tested are given. The Ki value is definedby the following formula:

$K_{i} = \frac{{IC}_{50}}{1 + \frac{\lbrack L\rbrack}{{EC}_{50}}}$

in which the IC₅₀ values are those concentrations of the compoundstested in μM by which 50% of the effect of compounds are antagonised.[L] is the concentration and the EC₅₀ value is the concentration of thecompounds in μM which brings about 50% stimulation.

The compounds of the present invention are mGluR5a receptor antagonists.The activities of compounds of formula I as measured in the assaydescribed above are in the range of K_(i)<100 μM.

The compounds of formula I and pharmaceutically acceptable salts thereofcan be used as medicaments, e.g. in the form of pharmaceuticalpreparations. The pharmaceutical preparations can be administeredorally, e.g. in the form of tablets, coated tablets, dragées, hard andsoft gelatine capsules, solutions, emulsions or suspensions. However,the administration can also be effected rectally, e.g. in the form ofsuppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and pharmaceutically acceptable salts thereofcan be processed with pharmaceutically inert, inorganic or organiccarriers for the production of pharmaceutical preparations. Lactose,corn starch or derivatives thereof, talc, stearic acid or its salts andthe like can be used, for example, as such carriers for tablets, coatedtablets, dragées and hard gelatine capsules. Suitable carriers for softgelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like; depending on the nature ofthe active substance no carriers are, however, usually required in thecase of soft gelatine capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, sucrose, invertsugar, glucose and the like. Adjuvants, such as alcohols, polyols,glycerol, vegetable oils and the like, can be used for aqueous injectionsolutions of water-soluble salts of compounds of formula I, but as arule are not necessary. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

In addition, the pharmaceutical preparations can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

As mentioned earlier, medicaments containing a compound of formula I orpharmaceutically acceptable salts thereof and a therapeutically inertexcipient are also an object of the present invention, as is a processfor the production of such medicaments which comprises bringing one ormore compounds of formula I or pharmaceutically acceptable salts thereofand, if desired, one or more other therapeutically valuable substancesinto a galenical dosage form together with one or more therapeuticallyinert carriers.

The dosage can vary within wide limits and will, of course, be fitted tothe individual requirements in each particular case. In general, theeffective dosage for oral or parenteral administration is between0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred forall of the indications described. The daily dosage for an adult humanbeing weighing 70 kg accordingly lies between 0.7-1400 mg per day,preferably between 7 and 700 mg per day.

The following examples are provided to further elucidate the invention:

EXAMPLE 1

-   (3,3-Dimethyl-morpholin-4-yl)-    [5-(3-fluoro-phenylethynyl)-pyridin-2-yl] -methanone

Step 1: 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid methylester

Bis-(triphenylphosphine)-palladium(II)dichloride (406 mg, 580 μmol, 0.05equiv.) was dissolved in 25 ml DMF. (2.5 g, 11.6 mmol)5-Bromo-pyridine-2-carboxylic acid methyl ester and3-fluorophenylacetylene (2.22 g, 18.5 mmol, 1.6 equiv.) were added atroom temperature. Triethylamine (3.5 g, 4.84 ml, 34.7 mmol, 3 equiv.),triphenylphosphine (91 mg, 347 μmol, 0.03 equiv.) and copper(I)iodide(66 mg, 347 μmol, 0.03 equiv.) were added and the mixture was stirredfor 20 hours at 80° C. The reaction mixture was cooled and evaporated todryness with Isolute® sorbent. The crude product was purified by flashchromatography on silica gel (70 g) eluting with an ethylacetate:heptane gradient 0:100 to 80:20. The desired5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid methyl ester (1.95g, 66% yield) was obtained as a light yellow solid, MS: m/e=256.3(M+H⁺).

Step 2: 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid

(1.9 g, 7.44 mmol) 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acidmethyl ester (Example 1, step 1) was dissolved in THF (30 ml) and water(30 ml) and LiOH (357 mg, 24.9 mmol, 2 equiv.) was added at roomtemperature. The mixture was stirred for 16 hours at room temperature.The reaction mixture was acidified with 4N HCl to pH 2.5 and THF wasevaporated to form a yellow suspension. The suspension was cooled to0-5° C. and filtered. The crystals were washed with cold water andevaporated to dryness. The desired5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid (1.71 g, 95%yield) was obtained as a light yellow solid, MS: m/e=239.9 (M+H⁺).

Step 3:(3,3-Dimethyl-morpholin-4-yl)[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-methanone

(50 mg, 0.21 mmol) 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid(Example 1, step 2) was dissolved in DMF (0.5 ml) and Hunig's Base (44μl, 0.31 mmol, 1.2 equiv.), 3,3-dimethylmorpholine (36 mg, 0.25 mmol,1.5 equiv.) and TBTU (73 mg, 0.23 mmol, 1.1 equiv.) were added at roomtemperature. The mixture was stirred for 16 hours at room temperature.The reaction mixture was evaporated and extracted saturated NaHCO₃solution and two times with a small volume of dichloromethane. The crudeproduct was purified by flash chromatography by directly loading thedichloromethane layers onto a silica gel column and eluting with anethyl acetate:heptane gradient 0:100 to 80:20. The desired(3,3-dimethyl-morpholin-4-yl)[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-methanone(61 mg, 87% yield) was obtained as a light yellow oil, MS: m/e=339.2(M+H⁺).

EXAMPLE 2

-   [5-(3-Chloro-phenylethynyl)-pyridin-2-yl-morpholin-4-yl]-methanone

Step 1: 5-(3-Chloro-phenylethynyl)-pyridine-2-carboxylic acid

The title compound was obtained as a white solid, MS: m/e=258.4/260.4(M+H⁺), using chemistry similar to that described in Example 1, step 1from 5-bromo-pyridine-2-carboxylic acid and 3-chlorophenylacetylene.

Step 2:[5-(3-Chloro-phenylethynyl)-pyridin-2-yl]-morpholin-4-yl-methanone

The title compound was obtained as a white solid, MS: m/e=327.5/329.5(M+H⁺), using chemistry similar to that described in Example 1, step 3from 5-(3-chloro-phenylethynyl)-pyridine-2-carboxylic acid (Example 2,step 1) and morpholine.

EXAMPLE 3

-   (3,3-Dimethyl-morpholin-4-yl)-[5-(3-chloro-phenylethynyl)-pyridin-2-yl]-methanone

The title compound was obtained as a white solid, MS: m/e=355.5/357.5(M+H⁺), using chemistry similar to that described in Example 1, step 3from 5-(3-chloro-phenylethynyl)-pyridine-2-carboxylic acid (Example 2,step 1) and 3,3-dimethylmorpholine.

EXAMPLE 4

-   (3,3-Dimethyl-morpholin-4-yl)-[5-(3-chloro-phenylethynyl)-pyrimidin-2-yl]-methanone

Step 1: 5-(3-Chloro-phenylethynyl)-pyrimidine-2-carboxylic acid

The title compound was obtained as a white solid, MS: m/e=259.4/261.4(M+H⁺), using chemistry similar to that described in Example 1, step 1from 5-bromo-pyrimidine-2-carboxylic acid and 3-chlorophenylacetylene.

Step 2:(3,3-Dimethyl-morpholin-4-yl)-[5-(3-chloro-phenylethynyl)-pyrimidin-2-yl]-methanone

(100 mg, 0.39 mmol) 5-(3-Chloro-phenylethynyl)-pyrimidine-2-carboxylicacid (Example 4, step 1) was suspended in dichloromethane (1 ml) and DMF(10 μl). Oxalyl chloride (51 μl, 0.59 mmol, 1.5 equiv.) was added dropwise at room temperature and the mixture was stirred for 1 hour atreflux. The reaction mixture was then added to a mixture ofdiisopropylethylamine (235 μl, 1.34 mmol, 3.3 equiv.) and3,3-dimethylmorpholine (46 mg, 0.40 mmol, 1 equiv.) in THF (2 ml). Themixture was stirred for 16 hours at room temperature and evaporated inpresence of Isolute® sorbent to dryness. The crude product was purifiedby flash chromatography with a 20 g silica gel column eluting withheptane:ethyl acetate 100:0->0:100. The desired(3,3-dimethyl-morpholin-4-yl)[5-(3-chloro-phenylethynyl)-pyrimidin-2-yl]-methanone(120 mg, 94% yield) was obtained as a white solid, MS: m/e=356.6/358.6(M+H⁺).

1. A compound of formula I

wherein Y is N or CH; R¹ is fluoro or chloro; R² is hydrogen or methyl;or a pharmaceutically acceptable acid addition salt, a racemic mixture,or its corresponding enantiomer and/or optical isomer and/orstereoisomer thereof.
 2. A compound of formula I according to claim 1,wherein Y is N.
 3. A compound of formula I according to claim 2, whichis(3,3-dimethyl-morpholin-4-yl)[5-(3-chloro-phenylethynyl)-pyrimidin-2-yl]-methanone.4. A compound of formula I according to claim 1, wherein Y is CH.
 5. Acompound of formula I according to claim 4, selected from(3,3-dimethyl-morpholin-4-yl)[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-methanone[5-(3-chloro-phenylethynyl)-pyridin-2-yl]-morpholin-4-yl-methanone and(3,3-dimethyl-morpholin-4-yl)[5-(3-chloro-phenylethynyl)-pyridin-2-yl]-methanone.6. A process for preparation of a compound of formula I as described inclaim 1, comprising reacting a compound of formula

with a compound of formula

to form a compound of formula I

wherein the substituents are described in claim
 1. 7. A compound made bythe method of claim
 6. 8. A pharmaceutical composition comprising acompound of claim 1 and a therapeutically active carrier.
 9. A method ofinhibiting metabotropic glutamate receptor mGluR5 in vitro comprisingcontacting the receptor with an effective amount of a compound ofclaim
 1. 10. A method of inhibiting metabotropic glutamate receptormGluR5 in vivo comprising administering to a patient in need thereof aneffective amount of a compound of claim
 1. 11. A method for thetreatment of anxiety, pain, depression, Fragile-X syndrome, an autismspectrum disorder, Parkinson's disease, or gastroesophageal refluxdisease (GERD), which method comprises administering an effective amountof a compound as defined in claim 1 to a patient in need thereof.